The human frontal cortex displays an accelerated phenotypic evolution in structural and functional complexity, and arguably contributes more than any other brain region to our cognitive and behavioral attributes. Consequently, the frontal cortex represents the most critical region in which to study the molecular and cellular bases of many psychiatric disorders. Our preliminary studies show that distinct areas of the human frontal cortex are distinguished from other cortical regions by the combinatorial expression of specific genes during the second trimester of gestation, and that microarray expression profiling can be used to identify further candidate genes for patterning of these areas. Our main hypothesis is that the patterning and development of the frontal cortex are associated with changes in the activity of genes, from embryonic stages to adolescence, and that these differentially expressed genes play critical roles in the formation and refinement of frontal cortical circuits. To identify such genes, we will use whole- genome exon microarrays and state-of-the-art bioinformatics to analyze temporal and spatial patterns of gene expression and alternative mRNA splicing in the developing human brain. Our studies will encompass all crucial stages of prenatal and postnatal development, including the first trimester, during which cortical neurons are generated; the second trimester, when cortical connections are starting to form; and the late fetal and early postnatal periods, when connections are organized to create functional circuits. Just as importantly, our studies will survey a comprehensive selection of brain regions for high spatial resolution of gene expression mapping, especially within the frontal lobe. PUBLIC HEALTH RELEVANCE: The identification of genes involved in formation and maturation of the frontal cortex as outlined in this proposal will help in understanding normal human brain development and plasticity as well as the neurobiological foundations of disorders such as schizophrenia, autism, and language impairment. This research may further facilitate the identification of disease genes and the development of new therapeutic strategies for the treatment of these disorders.